Human natural killer (NK) cells have been shown to be capable of inhibiting replication of Herpes Simplex Virus Type-1 (HSV-1) in fibroblasts and patient studies have implicated these effector cells as an important first-line defense mechanism against invading viral pathogens. In our studies proposed here, we will investigate the basic biology of natural kill of HSV-1 infected targets, concentrating on two aspects of this important host defense mechanism. The first of these objectives will examine the characteristics of the effector cells which lyse HSV-1 infected targets. Our previous studies indicated that functional heterogeneity exists among human NK cell populations, with apparently different effector cells responsible for lysis of K562 tumor targets and HSV-infected fibroblasts. Recent observations indicate that the apparent heterogeneity may be due in part to the requirement of NK(HSV-Fs) but not of NK(K562) effectors for an accessory cell function. In this study, we will characterize the necessary accessory cells and determine whether effector/accessory cell contact is required for activity and whether soluble factors are involved in the accessory cell function. We will also investigate the nature of effector cells responsible for kill of an HSV-1 infected lymphoblastoid cell line and determine whether lysis of these targets is more similar to that of the adherence-dependent HSV-Fs targets or to that of the suspension grown tumor cell line, K562. Our second objective will concentrate on the HSV-infected target cells and will characterize changes induced by infection that allow these cells to be recognized and killed by NK effector cells. The role of specific viral genes and possible changes in host cellular gene expression will be evaluated. In addition, we will compare the modifications of HSV-Fs vs. HSV-infected lymphoblastoid cells required for induction of NK lysis to determine whether the virus provides a universal signal recognizable as foreign by the NK cell or whether the context of viral expression is crucial for the recognition of HSV-infected targets. Together, these studies, involving target cells which are by themselves poorly lysed and an external signal which renders them susceptible to lysis, should provide us with greater insight into the nature of NK effector/target cell interactions.